Use of quantitative pharmacology in the development of HAE1, a high-affinity anti-IgE monoclonal antibody.
AAPS J
; 10(2): 425-30, 2008 Jun.
Article
em En
| MEDLINE
| ID: mdl-18686041
HAE1, a high-affinity anti-IgE monoclonal antibody, is discussed here as a case study in the use of quantitative pharmacology in the development of a second-generation molecule. In vitro, preclinical, and clinical data from the first-generation molecule, omalizumab, were heavily leveraged in the HAE1 program. A preliminary mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for HAE1 was developed using an existing model for omalizumab, together with in vitro binding data for HAE1 and omalizumab. When phase I data were available, the model was refined by simultaneously modeling PK/PD data from omalizumab studies with the available HAE1 phase I data. The HAE1 clinical program was based on knowledge of the quantitative relationship between a pharmacodynamic biomarker, suppression of free IgE, and clinical response (e.g., lower exacerbation rates) obtained in pivotal studies with omalizumab. A clinical trial simulation platform was developed to predict free IgE levels and clinical responses following attainment of a target free IgE level (=10 IU/ml). The simulation platform enabled selection of four doses for the phase II dose-ranging trial by two independent methods: dose-response non-linear fitting and linear mixed modeling. Agreement between the two methods provided confidence in the doses selected. Modeling and simulation played a large role in supporting acceleration of the HAE1 program by enabling data-driven decision-making, often based on confirmation of projections and/or learning from incoming new data.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Imunoglobulina E
/
Desenho de Fármacos
/
Anticorpos Monoclonais
/
Afinidade de Anticorpos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
AAPS J
Assunto da revista:
FARMACOLOGIA
/
TERAPIA POR MEDICAMENTOS
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos